The invention relates to novel soft steroids having anti-inflammatory activity, pharmaceutical compositions containing said soft steroids, novel chemical intermediates useful in the preparation of the steroids, and methods of administering said steroids to mammals in the treatment of inflammation.
Successful predictions on a rational basis of the biological activity of compounds leading to new drugs are the main objective of drug designers. This has usually been achieved by considering a known bioactive molecule as the basis for structural modifications, either by the group or biofunctional moieties approach or by altering the overall physical-chemical properties of the molecule. Thus, the main aim has been to design, synthesize, and test new compounds structurally analogous to the basic bioactive molecule which have, however, improved therapeutic and/or pharmacokinetic properties. Although xe2x80x9cvulnerablexe2x80x9d moieties have been identified as the ones whose role is the bioinactivation or metabolic elimination of the drug after it has performed its role, little or no attention has been paid in the drug-design process to the rational design of the metabolic disposition of the drugs. This has been the case despite the fact that the toxicity of a number of bioactive molecular is due to their increased elimination half-life, stability, or other factors introduced during the design of increasing their activity. Drugs and particularly their metabolic processes contribute to the various toxic processes by formation of active metabolites. The phenomenon of metabolic activation to reactive intermediates which covalently bind to tissue macromolecules is the initial step in cell damage. It is also clear that the most toxic metabolites will not survive long enough to be excreted and identified; thus, studies of the stable metabolites may provide misleading information.
It is clear that, in order to prevent and/or reduce toxicity problems related to drugs, the metabolic disposition of the drugs should be considered at an early stage of the drug-design process. This is true particularly when one considers that the body can attack and alter chemically quite stable structures and that, even if a drug is 95% excreted unchanged, the unaccounted small portion can, and most likely will, cause toxicity.
xe2x80x9cSoft drugsxe2x80x9d can be defined as biologically active chemical compounds (drugs) which might structurally resemble known active drugs (soft analogues) or could be entirely new types of structures, but which are all characterized by a predictable in vivo destruction (metabolism) to nontoxic moieties, after they achieve their therapeutic role. The metabolic disposition of the soft drugs takes place with a controllable rate in a predictable manner.
The present inventor has found five major classes of soft drugs. One of the most useful classes was termed the xe2x80x9cinactive metabolitexe2x80x9d approach which can be advantageously employed to design especially valuable xe2x80x9csoft drugsxe2x80x9d. This approach starts with a known inactive metabolite of a drug or a drug class; followed by modifying the metabolite to resemble structurally (isosteric and/or isoelectronic) the active drug (i.e., activation); and designing the metabolism of the activated species to lead to the starting inactive metabolite after achieving the desired therapeutic role, without the formation of toxic intermediates (i.e., predictable metabolism). The xe2x80x9cinactive metabolitexe2x80x9d approach further allows controlling the rate of metabolism and pharmacokinetic properties by molecular manipulation in the activation stage. Also, if no useful inactive metabolite is known, one can be designed by the introduction of transporting groups in noncritical structural parts.
The present inventor has now applied his inactive metabolite approach to the case of the natural and synthetic glucocorticosteroids and has designed the soft steroidal anti-inflammatory agents of the present invention, beginning with the known inactive natural metabolites of the glucocorticosteroids. Thus, for example, in the case of hydrocortisone, one of its major, inactive metabolites, cortienic acid, i.e., 11xcex2,17xcex1-dihydroxyandrost-4-en-3-one-17xcex2-carboxylic acid, has been used as a starting point and activated by the introduction of suitable non-toxic 17xcex1- and 17xcex2-substituents, which activated derivatives will cleave in vivo, after accomplishment of their therapeutic role, to the starting inactive metabolite and other nontoxic moieties.
In accord with the foregoing, the present invention provides novel soft steroids having anti-inflammatory activity, said steroids having the structural formula 
wherein:
R1 is C1-C10 alkyl; C2-C10 (monohydroxy or polyhydroxy)alkyl; C1-C10 (monohalo or polyhalo)alkyl; or xe2x80x94CH2COOR6 wherein R6 is unsubstituted or substituted C1-C10 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl or C2-C10 alkenyl, the substituents being selected from the group consisting of halo, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, 
or R6 is unsubstituted or substituted phenyl or benzyl, the substituents being selected from the group consisting of lower alkyl, lower alkoxy, halo, carbamoyl, lower alkoxycarbonyl, lower alkanoyloxy, lower haloalkyl, mono(lower alkyl)amino, di(lower alkyl)amino, mono(lower alkyl)carbamoyl, di(lower alkyl)carbamoyl, lower alkylthio, lower alkylsulfinyl and lower alkylsulfonyl; or R1 is xe2x80x94CH2CONR7R8 wherein R7 and R8, which can be the same or different, are each hydrogen, lower alkyl, C3-C8 cycloalkyl, phenyl or benzyl, or R7 and R8 are combined such that xe2x80x94NR7R8 represents the residue of a saturated monocyclic secondary amine; or R1 is unsubstituted or substituted phenyl or benzyl, the substituents being selected from the group of phenyl and benzyl substituents defined hereinabove with respect to R6; or R1 is 
wherein Y is xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94or xe2x80x94Oxe2x80x94 and R9 is hydrogen, lower alkyl or phenyl, or R9 and the lower alkyl group adjacent to Y are combined so that R1 is a cyclic system of the type 
wherein Y is defined as above and the alkylene group contains 3 to 10 carbon atoms, of which at least 3 and no more than 6 are ring atoms; or R1 is 
wherein R6 is defined as hereinabove and R10 is hydrogen, lower alkyl, phenyl or haloalkyl;
R2 is unsubstituted or substituted C1-C10 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl or C2-C10 alkenyl, the substituents being selected from the group consisting of halo, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, 
or R2 is unsubstituted or substituted phenyl or benzyl, the substituents being selected from the group consisting of lower alkyl, lower alkoxy, halo, carbamoyl, lower alkoxycarbonyl, lower alkanoyloxy, lower haloalkyl, mono(lower alkyl)amino, di(lower alkyl)amino, mono(lower alkyl)carbamoyl, di(lower alkyl)carbamoyl, lower alkylthio, lower alkylsulfinyl and lower alkylsulfonyl;
R3 is hydrogen, xcex1-hydroxy, xcex2-hydroxy, xcex1-methyl, xcex2-methyl, xe2x95x90CH2, or xcex1- or 
wherein R2 is identical to R2 as defined hereinabove;
R4 is hydrogen, fluoro or chloro;
R5 is hydrogen, fluoro, chloro or methyl;
X is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94;
Z is carbonyl or xcex2-hydroxymethylene;
and the dotted line in ring A indicates that the 1,2-linkage is saturated or unsaturated.
A group of preferred compounds of formula (I) consists of those wherein:
R1 is C1-C6 alkyl; C1-C6 (monohalo or polyhalo)alkyl; xe2x80x94CH2COOR6 wherein R6 is C1-C6 alkyl; xe2x80x94CH2xe2x80x94Yxe2x80x94(C1-C6 alkyl) wherein Y is xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94 or xe2x80x94Oxe2x80x94; or 
wherein R6xe2x80x2 is C1-C6 alkyl or phenyl;
R2 is C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, benzyl or C1-C6 (monohalo or polyhalo)alkyl;
R3 is hydrogen, xcex1-hydroxy, xcex1-methyl, xcex2-methyl or 
wherein R2 is identical to R2 as defined hereinabove;
R4 is hydrogen or fluoro;
R5 is hydrogen or fluoro;
Z is xcex2-hydroxymethylene;
and X and the dotted line in ring A are defined as hereinabove.
The invention further provides anti-inflammatory quaternary ammonium salts of selected compounds of formula (I), as discussed in further detail below. Novel intermediates to the compounds of formula (I), e.g., the corresponding compounds wherein R1 is hydrogen, are provided also.
The soft steroids of formula (I) and quaternary ammonium salts thereof are extremely potent local anti-inflammatory agents; however, by virtue of the fact that their facile in vivo destruction leads only to the inactive steroidal metabolite, the present compounds have far less systemic activity than the known glucocorticosteroids from whose inactive metabolites they are derived. Indeed, many of the compounds of the present invention are entirely devoid of systemic activity. Such minimalxe2x80x94or non-existentxe2x80x94systemic activity means that the compounds of the present invention can be used in the local (e.g., topical) treatment of inflammatory conditions without the serious systemic side effects which attend use of the known glucocorticosteroids.
With respect to the various groups encompassed by the generic terms used here and throughout this specification, the following definitions and explanations are applicable:
The alkyl, alkenyl and alkylene groupings can be straight or branched-chain groups containing the aforementioned number of carbon atoms. Likewise, the alkyl portions of the alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkanoyloxy, haloalkyl, monoalkylamino, dialkylamino, monoalkylcarbamoyl and dialkylcarbamoyl groupings each can be straight or branched-chain. The term xe2x80x9clowerxe2x80x9d used in conjunction with any of those groupings or in conjunction with xe2x80x9calkylxe2x80x9d is intended to indicate that each alkyl portion therein can contain 1 to 8 carbon atoms.
Specific examples of alkyl radicals encompassed by formula (I), whether as specific values for R1 or R2, or as a portion of a R1, R2, or R3 group, include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl and their branched-chain isomers, as well as their straight and branched-chain higher homologues in the instances where xe2x80x9calkylxe2x80x9d can contain more than 8 carbon atoms. The alkenyl radicals can be exemplified by vinyl, propenyl and butenyl. Illustrative of the cycloalkyl and cycloalkenyl radicals are cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl. The alkylene moieties are typified by trimethylene, tetramethylene and the like.
The alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkanoyloxy, monoalkylamino, dialkylamino, monoalkylcarbamoyl and dialkylcarbamoyl groupings are of the type
xe2x80x94O-alkyl
xe2x80x94S-alkyl
xe2x80x94SO-alkyl
xe2x80x94SO2-alkyl 
respectively, wherein alkyl is as hereinbefore defined and exemplified.
With respect to the structural variables encompassed by the group of preferred compounds of formula (I) identified hereinabove, the term xe2x80x9cC1-C6 alkylxe2x80x9d is used to refer to a straight or branched-chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like. In addition, the term xe2x80x9cC1-C6 (monohalo or polyhalo)alkylxe2x80x9d is used to refer to a straight or branched-chain alkyl group having 1 to 6 carbon atoms substituted with from 1 to 3 halogen atoms, the term xe2x80x9chalogenxe2x80x9d as used herein including a chlorine atom, a bromine atom, an iodine atom or a fluorine atom. Specific examples of the contemplated monohaloalkyl and polyhaloalkyl groups include chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1-chloroethyl, 2-chloroethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, 1,2-dichloroethyl, 1-chloropropyl, 3-chloropropyl, 1-chlorobutyl, 1-chloropentyl, 1-chlorohexyl, 4-chlorobutyl and the like. Also, the term xe2x80x9cC3-C8 cycloalkylxe2x80x9d is used to refer to a cycloalkyl radical having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
When R1 is formula (I) is xe2x80x94CH2CONR7R8 wherein xe2x80x94NR7R8 represents the residue of a saturated monocyclic secondary amine, such monocycles preferably have 5 to 7 ring atoms optionally containing another hetero atom (xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94Nxe2x80x94) in addition to the indicated nitrogen atom, and optionally bear one or more substituents such as phenyl, benzyl and methyl. Illustrative of residues of saturated monocyclic secondary amines which are encompassed by the xe2x80x94NR7R8 term are morpholino, 1-pyrrolidinyl, 4-benzyl-1-piperazinyl, perhydro-1,2,4-oxathiazin-4-yl, 1- or 4-piperazinyl, 4-methyl-1-piperazinyl, piperidino, hexamethyleneimino, 4-phenylpiperidino, 2-methyl-1-pyrazolidinyl, 1- or 2-pyrazolidinyl, 3-methyl-1-imidazolidinyl, 1- or 3-imidazolidinyl, 4-benzylpiperidino and 4-phenyl-1-piperazinyl.
Selected compounds of formula (I), i.e. compounds wherein R1 is xcex1-haloalkyl, readily form the corresponding soft quaternary ammonium salts which are likewise useful as soft anti-inflammatory agents. Thus, for example, the selected haloalkyl derivative of formula (I) can simply be reacted with a tertiary amine 
or an unsaturated amine 
to afford the corresponding quaternary ammonium salt. The reactants are generally used in approximately equimolecular proportions and the reaction is conducted in the presence of an inert solvent (e.g., ether, acetonitrile, CH2Cl2 or the like), at a temperature of from room temperature to the reflux temperature of the solvent, for approximately 2 to 24 hours. Alternatively, the reaction can be conducted in the absence of a solvent by mixing the two reactants together and maintaining them at room temperature or between 20xc2x0 to 70xc2x0 C. for 2 to 24 hours. In either case, the crystalline salt formed can be purified by crystallization from an ether-ethanol mixture, or the like.
The expression xe2x80x9cunsaturated aminexe2x80x9d used above denotes N-heterocyclic unsaturated systems having 3 to 10 members in the ring, and substituted derivatives thereof, where the unsaturation corresponds to the maximum number of no-cumulative double bonds, provided that the nitrogen atom contains no hydrogen atom as a substituent. The following examples will sufficiently illustrate the scope of the defined term: 
Substituted derivatives of the unsaturated amines include groups as shown above containing one or more alkyl, xe2x80x94COO(alkyl) or xe2x80x94OCO(alkyl) substituents.
With respect to the expression xe2x80x9ctertiary aminexe2x80x9d, this expression denotes amines wherein the nitrogen atom has no hydrogen atoms attached thereto and which are not among the N-heterocyclic unsaturated systems encompassed by the expression xe2x80x9cunsaturated aminexe2x80x9d as defined above. Typically, the term xe2x80x9ctertiary aminexe2x80x9d includes trialkylamines, wherein the alkyl groups, which can be the same or different, each preferably contain 1 to 8 carbon atoms; trialkoxyamines wherein the alkoxy portions each contain 1 to 8 carbon atoms; tertiary saturated cyclic amines such as quinuclidine or substituted quinuclidine (e.g., 3-acetoxyquinuclidine); and N-substituted derivatives of secondary saturated cyclic amines [e.g., an N-substituted derivative of morpholine, pyrrolidine, imidazolidine, pyrazolidine, piperidine or piperazine, wherein the N-substituent can be a group such as (C1-C8)alkyl], optionally containing additional substituents such as methyl.
Preferred quaternary ammonium salts include those derived from 1,2-dimethylpyrrolidine, 3-acetoxyquinuclidine, 1-methylpyrrolidine, triethylamine and N-methylimidazole. Especially preferred are the quaternary ammonium salts derived from the reaction of the aforesaid amines with compounds of formula (I) wherein Z is xcex2-hydroxymethylene and R1 is chloromethyl, most especially when R2 is lower alkyl.
While all of the compounds encompassed by formula (I) above essentially satisfy the objectives of the present invention, nevertheless certain groups of compounds remain preferred. A xe2x80x9cfirstxe2x80x9d group of preferred compounds of formula (I) has been set forth in the Summary of the Invention hereinabove.
Another preferred group of compounds consists of the compounds of formula (I) wherein Z, X, R1 and R2 are defined as hereinabove, and the remainder of the structural variations are identical to those of hydrocortisone (i.e., R3, R4 and R5 are each a hydrogen atom and the 1,2-linkage is saturated) or of prednisolone (i.e., R3, R4 and R5 are each a hydrogen atom and the 1,2-linkage is unsaturated), most especially when R1 and R2 are as defined with respect to the xe2x80x9cfirstxe2x80x9d group of preferred compounds set forth hereinabove.
Another preferred group of compounds consists of the 6xcex1- and/or 9xcex1-fluoro and 16xcex1- or 16xcex2-methyl congeners of the compounds indicated in the preceding paragraph. Within this group, the compounds wherein Z, X, R1 and R2 are defined as hereinabove and the remaining structural variables are identical to those of fludrocortisone, betamethasone and dexamethasone are particularly preferred, most especially when R1 and R2 are as defined with respect to the xe2x80x9cfirstxe2x80x9d group of preferred compounds set forth hereinabove. Other compounds of particular interest within this group are those wherein Z, X, R1 and R2 are defined as hereinabove and the remaining structural variables are identical to those of triamcinolone, flumethasone, fluprednisolone or paramethasone, particularly when R1 and R2 are as defined with respect to the xe2x80x9cfirstxe2x80x9d group of preferred compounds set forth hereinabove. Yet other interesting compounds are those wherein Z, X, R1 and R2 are defined as hereinabove, R3 is 
and the remaining structural variables are identical to those of triamcinolone, particularly when R1 and R2 are as defined with respect to the xe2x80x9cfirstxe2x80x9d group of preferred compounds set forth hereinabove.
In each of the groups of compounds indicated in the three preceding paragraphs, the compounds wherein X is oxygen are particularly preferred. Most especially preferred are the compounds encompassed by the groups indicated above wherein Z is xcex2-hydroxymethylene, wherein X is oxygen, wherein R2 is C1-C6 alkyl (particularly methyl, ethyl, propyl or isopropyl), and wherein R1 is C1-C6 alkyl, C1-C6 (monohalo)alkyl (particularly chloromethyl) or xe2x80x94CH2xe2x80x94Yxe2x80x94(C1-C6 alkyl) wherein Y is defined as hereinabove (particularly when the C1-C6 alkyl group is methyl).
The compounds of formula (I) can generally be prepared by known methods, the method of choice being dependent on the identity of the various substituents in the desired final product.
One generally useful method for the preparation of the compounds of formula (I) wherein Z is xcex2-hydroxymethylene and X is oxygen utilize steroidal starting materials of the formula 
wherein R4, R5 and the dotted line in ring A are defined as before and R3xe2x80x2 is hydrogen, xcex1-methyl, xcex2-methyl, xcex1-OH, xcex2-CH or xe2x95x90CH2 (and which can be conveniently prepared by treatment of the corresponding 21-hydroxypregnenolones of the formula 
wherein R4, R5, R3xe2x80x2 and the dotted line in ring A are defined as above with NaIO4 in a suitable organic solvent at room or elevated temperature.) According to this process of the invention, a starting material of formula (II) is reacted with R2OCOCl or R2OCOBr (formed by reacting R2OH with COCl2 or COBr2, wherein R2 is defined as above), under anhydrous conditions, in an appropriate inert organic solvent such as dichloromethane, chloroform or tetrahydrofuran, preferably in the presence of a suitable acid acceptor (e.g., triethylamine, pyridine, calcium carbonate or other appropriate base). Time and temperature are not critical factors; however, the reaction is conveniently carried out at a temperature between 0xc2x0 C. and room temperature, for about 1 to 6 hours. The resultant novel 17xcex2-carboxylic acid 17xcex1-carbonate has the formula 
wherein R2, R4, R5 and the dotted line in the A ring are defined as above and R3xe2x80x3 is H, xcex1-CH3, xcex2-CH3, xcex1-OCOOR2, xcex2-OCOOR2 or xe2x95x90CH2. When R3xe2x80x2 in the starting material of formula (II) is xcex1-OH or xcex2-OH, sufficient R2OCOCl or R2OCOBr is generally employed to ensure formation of the carbonate grouping at the 16-position as well as at the 17-position [i.e., when R3xe2x80x2 in formula (II) is OH, R3xe2x80x3 in the resultant intermediate of formula (III) is xcex1- or xcex2-OCOOR2].
Sometimes, when a compound of formula (I) wherein R2 contains a sulfinyl or sulfonyl grouping is desired, such a grouping is not introduced via the R2OCOCl/R2OCOBr reaction, but is prepared from the corresponding thio-containing R2 derivative at a later stage in the synthetic scheme, as well be discussed in more detail below.
After the above-described introduction of the 17xcex1-substituent, the resultant novel intermediates of formula (III) is converted to its corresponding metal salt of the formula 
wherein R2, R3xe2x80x3, R4, R5 and the dotted line in the ring A are defined as above, and M is a suitable metal, e.g. alkali metal (such as sodium or potassium), alkaline earth metal/2, or thallium or NH4+. The novel salt of formula (IV) is typically formed by reacting the steroid of formula (III) with a hydroxide (MOH) or alkoxide (MOR) in an appropriate organic solvent, such as ethyl ether or tetrahydrofuran, at a temperature of 0xc2x0 C. to room temperature, for 0.5 to 4 hours. Then, the salt of formula (IV) is reacted with a compound of the formula R1-W wherein R1 is defined as hereinabove and W is halogen, to afford the desired final product of formula (I). This step of the reaction sequence can be conveniently conducted at room temperature for about 1 to 24 hours, or at the boiling of the solvent (i.e. acetonitrile, THF, etc.) When it is desired to introduce a halo-substituted R1 grouping into the steroid, e.g., when a compound of formula (I) wherein R1 is chloromethyl is desired, it has been found that the reaction proceeds well using hexamethylphosphoramide as the solvent at lower temperatures (0-10xc2x0 C.) and employing a R1-W reactant wherein W is iodine (e.g., iodochloromethane). When a non-halogen containing R1 grouping is desired (e.g., R1xe2x95x90alkyl or xe2x80x94CH2COOR6 where R6 is alkyl, etc.), no such restrictions need be placed on the R1-W reactant or on the solvent; thus, W can be any halogen, preferably chloro or bromo, and the usual organic solvents such as dimethylformamide, dichloromethane, acetonitrile, tetrahydrofuran or chloroform can, if desired, be used instead of hexamethylphosphoramide. When a compound of formula (I) wherein R1 contains a sulfinyl or sulfonyl grouping is desired, such a grouping is not generally introduced via the R1-W reaction, but is subsequently prepared from the corresponding thio steroid, as described below.
The compounds of formula (I) wherein R1 (or R2) is a sulfinyl- or sulfonyl-containing grouping can be prepared by oxidation of the corresponding thio steroids. Thus, for example, a compound of formula (I) wherein R1 is 
[wherein R9 is H, lower alkyl, or combined with the lower alkyl group adjacent to S to form a cyclic system, as described hereinabove] can be reacted with 1 equivalent of m-chloroperoxybenzoic acid at 0xc2x0-25xc2x0 C. for 1 to 24 hours, in a suitable solvent such as chloroform, to afford the corresponding compound of formula (I) wherein R1 is 
or with 2 equivalents of m-chloroperoxybenzoic acid to afford the corresponding compound of formula (I) wherein R1 is 
This type of reaction can also be utilized to prepare compounds of formula (I) wherein R1 is xe2x80x94CH2COOR6 wherein R6 is substituted alkyl, cycloalkyl, cycloalkenyl, alkenyl, phenyl, or benzyl, wherein the substituent is lower alkylsulfinyl or lower alkylsulfonyl, from the corresponding lower alkylthio-substituted formula (I) steroids; to prepare compounds of formula (I) wherein R1 is lower alkylsulfinyl- or alkylsulfonyl-substituted phenyl or benzyl from the corresponding lower alkylthio-substituted formula (I) steroids; and to prepare compounds of formula (I) wherein R2 is substituted alkyl, cycloalkyl, cycloalkenyl, alkenyl, phenyl or benzyl wherein the substituents is lower alkylsulfinyl or lower alkylsulfonyl, from the corresponding lower alkylthio-substituted formula (I) steroids.
When the compounds of formula (I) wherein R3 is xcex1- or xcex2-hydroxy are desired, same can be prepared by partial acid hydrolysis of the corresponding compounds of formula (I) wherein R3 is xcex1- or xcex2-OCOOR2, in a suitable solvent medium. Use of a mild reagent, e.g., oxalic acid in methanol, is desirable. Alternatively, hydrolysis of the 16-carbonate to the 16-hydroxy compound could be carried out at an earlier stage in any synthetic scheme described herein after the introduction of the 16,17-carbonate groupings, e.g., selective hydrolysis of an intermediate of formula (III) having 16 and 17 carbonate groupings to the corresponding 16-hydroxy and 17-carbonate, followed by conversion to the corresponding compound of formula (I) as described supra.
Another process for the preparation of the compounds of formula (I) wherein Z is xcex2-hydroxymethylene and X is oxygen utilizes the same 17xcex1-hydroxy-17xcex2-carboxylic acid starting materials of formula (II) as are employed in the synthetic scheme described supra, but involves formation of the 17xcex2-COOR1 grouping prior to, rather than after, introduction of the 17xcex1-OCOOR2 substituent. Essentially, the same non-steroidal reactants, reaction conditions, etc., as described above are used for the introduction of each group. Thus, the starting material of formula (II) is first reacted with MOH or MOR to form the corresponding intermediate of the formula 
wherein R3xe2x80x2, R4, R5 and M and the dotted line in ring A are defined as above, which is then reacted with R1W wherein R1 and W are defined as above, to afford the corresponding 17xcex2-carboxylate of the formula 
wherein R1, R3xe2x80x2, R4, R5 and the dotted line in ring A are defined as above, which is in turn reacted with R2OCOCl or R2OCOBr wherein R2 is defined as above, to afford the corresponding 17xcex1-carbonate of formula (I). The various parameters of the process of converting (II) to (V) are the same as those discussed in detail above with respect to the conversion of (III) to (IV). Likewise, the process parameters for converting (V) to (VI) parallel those detailed above with respect to converting (IV) to (I). Similarly, the process parameters for converting (VI) to (I) are basically the same as those given above for the conversion of (II) to (III). Thus, again when the starting material contains a 16-hydroxy group, the 16,17-dicarbonate of formula (I) will be formed which can then be selectively hydrolyzed, if desired, to the corresponding 16-hydroxy-17-carbonate of formula (I). And, again, the compounds of formula (I) in which R1 or R2 is a sulfinyl- or sulfonyl-containing grouping can be conveniently prepared by oxidation of the corresponding thio-containing compounds of formula (I) as detailed hereinabove. Alternatively, the compounds of formula (I) wherein R1 is a sulfinyl- or sulfonyl-containing group [e.g., when R1 is 
can be prepared by oxidation, preferably with m-chloroperoxybenzoic acid, of the corresponding compounds of formula (VI) in which R1 is a thio-containing group, followed by introduction of the 17xcex1-OCOOR2 substituent to the resultant sulfinyl or sulfonyl compound.
Another possible process for the preparation of the compounds of the present invention, which can be used to prepare compounds of formula (I) wherein Z is xcex2-hydroxymethylene and X is oxygen or sulfur, utilizes the 17xcex2-carboxylic acid 17xcex1-carbonate intermediates of formula (III) above. According to this process, an intermediate of formula (III) is successively treated, first with a mild acyl chloride forming agent, e.g. such as diethylchlorophosphate or oxalyl chloride, to form the corresponding novel acid chloride of the formula 
wherein R2, R3xe2x80x3, R4, R5 and the dotted line in ring A are defined as above, and then with R1XMxe2x80x2 wherein R1 and X are defined as before, and Mxe2x80x2 is hydrogen or M (M is defined as above), in an inert solvent (e.g., CHCl3, THF, acetonitrile or DMF), at a temperature between about 0xc2x0 C. and the boiling point of the solvent, for 1 to 6 hours, to afford the corresponding compound of formula (I). When using a compound of the formula R1XMxe2x80x2 wherein Mxe2x80x2 is hydrogen, an acid scavenger such as triethylamine is preferably present in the reaction system. The two steps of this process can be very conveniently run in the same solvent, without isolating the acid chloride of formula (VIII) formed in the first step. This process is of particular value when a compound of formula (I) wherein X is S is desired.
Yet another desirable process for the preparation of the compounds of formula (I) wherein Z is xcex2-hydroxymethylene and X is oxygen utilizes the 17xcex1-hydroxy-17xcex2-carboxylates of formula (VI) above. According to this process, an intermediate of formula (VI) is reacted with phosgene, in a suitable organic solvent (e.g., toluene, benzene, CH2Cl2 or acetonitrile) at a low temperature (xe2x88x9220xc2x0 C. to room temperature, e.g., 0xc2x0 C.), for about 2 hours (or until the reaction is complete). Evaporation to remove solvent and excess phosgene affords the desired novel 17xcex1-chlorocarbonyloxy-17xcex2-carboxylate intermediate of the formula 
wherein R1, R4, R5 and the dotted line in ring A are defined as above, R3xe2x80x3xe2x80x2 is hydrogen, xcex1-methyl, xcex2-methyl, xcex1-OCOCl, xcex2-OCOCl or xe2x95x90CH2. When R3xe2x80x2 in the starting material of formula (VI) is hydroxy, sufficient phosgene is generally employed to ensure formation of the chlorocarbonyloxy grouping at the 16-position as well as the 17-position [i.e., when R3xe2x80x2 in formula (VI) is a xcex1-OH or xcex2-OH, R3xe2x80x3xe2x80x2 in the resultant intermediate of formula (VII) is xcex1- or xcex2-OCOCl]. The intermediate of formula (VII) is then reacted with a compound of the formula R2OMxe2x80x2 wherein R2 and Mxe2x80x2 are defined as above, in an inert solvent, preferably in the presence of an acid scavenger (e.g. triethylamine), to afford the corresponding compound of formula (I). When R2OMxe2x80x2 is an alcohol of the formula R2OH, the reaction is conducted under the same conditions as in the reaction for conversion of compound (II) to compound (III). On the other hand, if a compound of the formula R2OM is employed as R2OMxe2x80x2, the reaction conditions are described as above for conversion of compound (VIII) to compound (I). When R3xe2x80x3xe2x80x2 in the formula (VII) is OCOCl, sufficient R2OMxe2x80x2 is generally utilized to ensure conversion of both the 16- and 17xcex1-substituents to OCOOR2 groupings in the final product. And, again, the 16-hydroxy and the sulfinyl- and sulfonyl-containing compounds of formula (I) are most conveniently formed as a final step in the synthetic scheme.
As a variation of the process described immediately above, a steroidal 17xcex1-hydroxy-17xcex2-carboxylic acid starting material of formula (II) can be reacted with phosgene as described above, to afford the 17xcex1-chlorocarbonyloxy-17xcex2-carboxylic acid intermediate of the formula 
wherein R3xe2x80x3xe2x80x2, R4, R5 and the dotted line in ring A are defined as above, which can then be reacted with R2OMxe2x80x2 as described supra, to afford the corresponding compound of formula (III) above. The novel intermediate can then be converted to a corresponding compound of formula (I) as described supra. Once again, the 16-hydroxy and the sulfinyl and sulfonyl derivatives are best prepared as a final step.
Still another process for the preparation of the compounds of formula (I) wherein Z is xcex2-hydroxymethylene and X is oxygen utilizes the 17xcex1-hydroxy-17xcex2-carboxylates of formula (VI) above. In accord with this method, an intermediate of formula (VI) is reacted with an excess amount of a carbonate of the formula 
(which can be conveniently prepared by reacting phosgene with 2 equivalents of R2OH) in the presence of an acid catalyst, to afford the corresponding compound of formula (I). Depending on the nature of the R2 grouping, the 
reactant can also act as the solvent at the boiling point of the carbonate reactant, or at the boiling point of the corresponding R2OH (which can conveniently be removed in this way from the reaction mixture, driving the reaction to completion), or the reactants can be combined in an appropriate inert organic solvent (e.g., an aromatic such as benzene or toluene, or a halogenated hydrocarbon such as dichloromethane or chloroform). And, again, the 16-hydroxy and the sulfinyl and sulfonyl compounds of formula (I) can conveniently be prepared as a final step in the process, although the intermediate of formula (VI) in which R1 contains a sulfur atom could be first oxidized, and the resultant sulfinyl or sulfonyl compound of formula (VI) then reacted with 
Other procedures for the preparation of selected compounds of formula (I) will be apparent to those skilled in the art. By way of example, a compound of formula (I) wherein R1 or R2 is halo-substituted can be subjected to a halogen exchange reaction in order to replace the halogen with a different halogen according to the order of reactivity Cl less than Br less than I. For example, reacting a chloroalkyl 17xcex2-carboxylate of formula (I) with an alkali metal iodide, e.g., sodium iodide, will afford the corresponding iodoalkyl 17xcex2-carboxylate. Similarly, a bromide salt (e.g., lithium bromide) can be reacted with a chloroalkyl 17xcex2-carboxylate to give the corresponding bromoalkyl 17xcex2-carboxylate. A suitable solvent for either reaction may be selected from the group consisting of hexamethylphosphoramide, acetone, ethanol, methyl ethyl ketone, dimethylacetamide, dimethylformamide and acetonitrile.
In like manner, a halogen exchange reaction based on relative solubilities can be used to convert a chloroalkyl 17xcex2-carboxylate or an iodoalkyl 17xcex2-carboxylate of formula (I) to the corresponding fluoroalkyl derivative. Silver fluoride can be employed in this reaction, which is conducted in a suitable organic solvent (e.g., acetonitrile), and which is especially useful in the preparation of the compounds in which R1 is fluoromethyl or fluoroethyl.
The 21-hydroxypregnenolones from which the steroidal starting materials of formula (II) are prepared can be obtained commercially or prepared by known methods. Likewise, the non-steroidal starting materials used in the various processes discussed above are commercially available or can be prepared by known chemical procedures.
Also, a starting material of formula (II) above can be reacted with a compound of the formula R2OCOCl or R2OCOBr wherein R2 is as defined above, to afford an intermediate of the formula 
wherein R2, R3xe2x80x3, R4, R5 and the dotted line in ring A are defined as above, which can be converted to the corresponding intermediate of formula (III) above by partial hydrolysis, with or without isolation of the compound of formula (XI). This reaction of a starting material of formula (II) with R2OCOCl or R2OCOBr can be carried out under the same conditions as the reaction of a compound of formula (II) with R2OCOCl or R2OCOBr as described hereinabove, except that R2OCOCl or R2OCOBr is used in an amount of 2 moles or more to one mole of the compound of the formula (II). The partial hydrolysis of the resultant compound of the formula (XI) can be carried out in an inert solvent in the presence of a catalyst. Examples of suitable catalysts include tertiary alkyl amines such as triethylamine, trimethylamine or the like; aromatic amines such as pyridine, 4,4-dimethylaminopyridine, quinoline or the like; secondary alkyl amines such as diethylamine, dimethylamine or the like; and inorganic bases such as sodium hydroxide, potassium hydroxide, potassium bicarbonate, or the like. Preferably, pyridine and potassium bicarbonate are employed. Examples of suitable inert solvents for use in the hydrolysis include water; lower alcohols such as ethanol, methanol or the like; ethers such as dimethyl ether, diethyl ether, dimethoxyethane, dioxane, tetrahydrofuran, or the like; halogenated hydrocarbons such as dichloromethane, chloroform or the like; tertiary amines such as pyridine, triethylamine or the like; or a mixture of two or more of the solvents mentioned above. The reaction is usually carried out a temperature of from about 0 to 100xc2x0 C., preferably at room temperature to 50xc2x0 C., for 1 to 48 hours, preferably for 2 to 5 hours.
In yet another aspect, the present invention provides novel compounds of the formula 
wherein R1, R2, R3, R4, R5, X and the dotted line in ring A are as defined with respect to formula (I) above. The 11-keto compounds of formula (IX) can be prepared by the procedures described hereinabove for the preparation of the corresponding 11xcex2-hydroxy compounds of formula (I). Thus, a starting material corresponding to formula (II) but having an 11-keto group is reacted with R2OCOCl or R2OCOBr, to afford the corresponding novel intermediate corresponding to formula (III) but having an 11-keto group; that intermediate is then converted to its metal salt, which corresponds to formula (IV) except for the presence of an 11-keto instead of an 11xcex2-hydroxy group; and the metal salt is then reacted with R1W to afford the corresponding compound of formula (IX). All reaction conditions are as previously described with respect to the corresponding processes for preparing the corresponding compounds of formula (I). Also, the preparation of the compounds of formula (IX) wherein R1 is a sulfinyl- or sulfonyl-containing grouping or wherein R3 is hydroxy generally proceeds as a final step in the synthetic scheme in a manner analogous to that used for the corresponding compounds of formula (I). Further, all of the above-described alternative processes for the preparation of the compounds of formula (I) are equally applicable to the preparation of the compounds of formula (IX) by simply substituting the 11-oxo starting material for the corresponding 11xcex2-hydroxy steroids used therein, e.g., replacing the 11-hydroxy group in formulas (V), (VI), (VII), (VIII), (X) and (XI) with an 11-oxo group and otherwise proceeding as described hereinabove for the reactions (II)xe2x86x92(V)xe2x86x92(VI)xe2x86x92(I); (III)xe2x86x92(VIII)xe2x86x92(I); (VI)xe2x86x92(VIII)xe2x86x92(I); (II)xe2x86x92(X)xe2x86x92(I); (VI)xe2x86x92(I), etc.
Also, the compounds of formula (IX) can be prepared by reacting the corresponding compounds of formula (I) with an oxidizing agent. The oxidation of a compound of formula (I) in order to convert it into the corresponding compound of formula (IX) is usually carried out by using an oxidizing agent in an appropriate solvent. The solvent may be any conventional solvent, for example, water, an organic acid (e.g. formic acid, acetic acid, trifluoroacetic acid), an alcohol (e.g. methanol, ethanol), a halogenated hydrocarbon (e.g. chloroform, dichloromethane), or the like. The oxidizing agent may also be any conventional agent which is effective for oxidizing a hydroxy group to a carbonyl group, for example, pyridinium chlorochromate, chromium trioxide in pyridine, hydrogen peroxide, dichromic acid, dichromates (e.g. sodium dichromate, potassium dichromate), permanganic acid, permanganates (e.g. sodium permanganate, potassium permanganate), or the like. The oxidizing agent is usually used in an amount of 1 mole or more, preferably 1 to 3 mole, per mole of the compound of formula (I). The reaction is usually carried out at a temperature of 0 to 40xc2x0 C., preferably at around room temperature, for about 6 to 30 hours.
The novel compounds of formula (IX) are useful as soft steroidal anti-inflammatory agents and also in vivo or in vitro precursors of the corresponding 11xcex2-hydroxy compounds. Thus, the compounds of formula (IX) can be reduced in vitro to afford the corresponding compounds of formula (I), using a reducing agent known to be capable of reducing the 11-oxo group to an a 11xcex2-hydroxy group without modifying the remainder of the steroidal starting material. Typically, microbiological reduction is advantageous for carrying out the desired conversion, although chemical reduction also is possible. Further, the compounds of formula (IX) may be formulated into appropriate dosage forms (e.g., retention enemas) for the treatment of conditions such as ulcerative colitis. In such dosage forms, it is thought that the compounds of formula (IX) are microbiologically reduced by bacteria in the body (e.g. in the colon) to the highly active 11xcex2-hydroxy steroids, which elicit the desired anti-inflammatory response.
The preferred compounds of formula (IX) are those which are precursors of the preferred compounds of formula (I) where Z is xcex2-hydroxymethylene, namely corresponding 11-keto compounds of formula (IX). An especially preferred group of compounds of formula (IX) consists of those wherein X, R1 and R2 are defined as above with respect to formula (I) and the remaining structural variations are identical to those of cortisone (i.e. R3, R4 and R5 are each a hydrogen atom and the 1,2-linkage is saturated), of prednisone (i.e. R3, R4 and R5 are each hydrogen and the 1,2-linkage is unsaturated), or of the 6xcex1- and/or 9xcex1-fluoro and the 16xcex1- or 16xcex2-methyl congeners thereof, particularly when R1 and R2 are as defined with respect to the xe2x80x9cfirstxe2x80x9d group of preferred compounds set forth hereinabove. Most especially preferred of these derivatives are those wherein X is oxygen, R2 is C1-C6 alkyl and R1 is C1-C6 alkyl, C1-C6 (monohalo)alkyl [particularly chloromethyl] or xe2x80x94CH2xe2x80x94Yxe2x80x94(C1-C6 alkyl) [particularly xe2x80x94CH2xe2x80x94Yxe2x80x94CH3].
The results of various activity studies of representative species of the invention, discussed in detail below, clearly indicate the potent anti-inflammatory activity and the minimal systemic activity/toxicity of the soft steroids of formula (I). In view of this desirable separation of local and systemic activities, the compounds of the invention can be used in the treatment of topical or other localized inflammatory conditions without causing the serious systemic side effects typically exhibited by the known natural and synthetic glucocorticosteroids such as cortisone, hydrocortisone, hydrocortisone 17xcex1-butyrate, betamethasone 17-valerate, triamcinolone, betamethasone dipropionate and the like.
The test animals were female Sprague/Dawley rats weighing approximately 40-45 grams each. One side of each ear of each rat was treated with a total of 25 microliters of a solution (ethanol/isopropyl myristate or acetone/isopropyl myristate, 90/10) containing the amount of test compound indicated below. Animals which were treated identically, save for omission of the test compound, served as controls. After 24 hours, all rats were sacrificed and weighed, and their thymi were removed and weighed. The results are tabulated in Table I below, the weights of the thymi being expressed as mg/100 g of rat.
The change in weight in the thymi is a measure of systemic activity and hence of toxicity. The lower the weight of the thymi, the greater the systemic activity. As can be seen from the above data, even hydrocortisone, the natural glucocorticoid, causes a significant decrease in thymus weight compared to the control. The decreases caused by equal doses of representative species of the invention are much less significant, indicating those compounds have much less systemic activity than hydrocortisone.
McKenzie-type human blanching studies were undertaken to study the blanching effects of a representative test compound of the invention, chloromethyl 17xcex1-ethoxycarbonyloxy-11xcex2-hydroxyandrost-4-en-3-one-17xcex2-carboxylate. The ability of a compound to cause blanching in humans has been found to correlate closely with its anti-inflammatory activity.
The test compound was dissolved in ethanol/isopropyl myristate (90/10 or 70/30) at 0.03, 0.01, 0.003, 0.001 and 0.0003 M concentrations. 50 Microliter aliquots of each solution were applied to separate gauze portions of a bandage of the type commonly used for allergy testing and the bandage was applied to the forearm. After 6 hours of occlusion, the bandage was removed. After 1 to 5 hours after removal of the bandage, blanching was observed even at the lowest concentrations of test compound.
When hydrocortisone was tested according to the above procedure comparing it directly to the test compound, blanching was not observed at concentrations of hydrocortisone below 0.03 M. Further, it was noted that 0.03 M hydrocortisone caused approximately the same degree of blanching as that resulting from use of 0.001 M chloromethyl 17xcex1-ethoxycarbonyloxy-11xcex2-hydroxyandrost-4-en-3-one-17xcex2-carboxylate.
The test animals were Sprague/Dawley rats weighing approximately 150 grams each. In treatment groups, selected amounts of the test compound were dissolved in acetone containing 5% croton oil and 50 microliters of the solution were applied to the inner surface of the right ear of the rats. A control group was identically treated with vehicle only, i.e. 5% croton oil in acetone. Six hours after croton oil challenge, a constant region of each ear was removed by dissection under anesthesia. Then, 48 hours after steroid treatment, the animals were sacrificed and the thymi and adrenals were removed and weighed. The test results showing the inhibitory effect of topically applied steroids on the ear swelling induced by croton oil are summarized in Table II below.
As can be seen from Table II above, the representative species of the present invention, namely chloromethyl 17xcex1-ethoxycarbonyloxy-11xcex2-hydroxyandrost-4-en-3-one-17xcex2-carboxylate, substantially inhibited the swelling (and consequent increased weight) of the ear caused by croton oil, i.e., the compound exhibited substantial anti-inflammatory activity. On the other hand, in contrast to the effect caused by betametasone 17-valerate, the representative compound of the invention did not significantly decrease the thymus weight as compared to the control, i.e., it did not show a significant degree of systemic activity.
The test compound was dissolved in acetone and aliquots of varying concentrations were injected into cotton pellets. The pellets were dried and then one pellet was implanted beneath the skin of each test rat. Six days later, the animals were sacrificed and the granulation tissue (granuloma) which formed in and around the implanted pellet was removed, dried and weighed. In addition, the thymi and adrenals were removed and weighed. The ability of a compound to inhibit granuloma formulation in this test is a direct indication of local anti-inflammatory activity; thus, the lower the weight of granulation tissue, the better the anti-inflammatory activity. On the other hand, a significant decrease in thymus weight is indicative of significant systemic activity; conversely, when a test compound does not significantly decrease thymus weight as compared to the control, such is indicative of a lack of (or very minimal) systemic side effects.
The results are tabulated in Tables III, IV and V-a and V-b below.
The test data in Tables III, IV and V-a and V-b above clearly show that the representative compounds of the present invention exhibited a significant anti-inflammatory response at lower dosages than did the prior art steroids, hydrocortisone 17-butyrate and betamethasone 17-valerate. On the other hand, all of the prior art steroids dramatically decreased the weight of the thymi and thus showed very potent systemic activity, while the representative compounds of the invention either did not significantly decrease the thymi weights or only minimally decreased the thymi weight. Thus, the present compounds have a much greater therapeutic index, i.e., separation of local anti-inflammatory from systemic activity, than do the prior art steroidal anti-inflammatory agents.
Also the test data in Table V-b above shows that the representative compounds of the present invention exhibited a significant local anti-inflammatory activity.
From the results tabulated in Tables IV and V-b, the ED40""s, ED50""s and ED60""s and the relative potencies of representative compounds of the invention were calculated and are shown in Table VI below. One of the compounds of the invention, namely chloromethyl 11-hydroxy-17-isopropoxycarbonyloxyandrost-4-en-3-one-17-carboxylate, has been assigned a potency value of 1 at each ED level, and the potencies of the other compounds are expressed relative thereto. The ED40""s, ED50""s and ED60""s are the dosages required to achieve, respectively, 40%, 50% and 60% reduction in the weight of the granulation tissue.
Several further studies were undertaken to determine the effects of selected compounds of the invention on thymi weights in rats when the drugs were systemically administered. In each of these studies, male Sprague-Dawley rats were used. (For average weight of rats for each study, see the tables which follow.) The test compounds were suspended in 0.5% CMC (carboxymethylcellulose) and injected subcutaneously once daily for three days. On the fifth day (48 hours following the last treatment), the animals were sacrificed and the thymi weights were recorded. Body weight gains were measured 24 hours after the last treatment. The test results are set forth in Tables VII, VIII and IX below. The TED40""s, TED50""s (thymolytic effective doses or doses required to achieve 40% and 50% inhibition of thymi weight, respectively) and relative potency of representative compounds of the invention and reference steroids are shown in Table X below. In Table X, the TED40 and TED50 for the reference steroid betamethasone 17-valerate has each been assigned a value of 1, and the potencies of the other compounds are expressed relative thereto. It is evident that the higher the inhibition of thymus activity at a given dose, the more toxic the compound is.
A further test was undertaken to determine the thymolytic activity of a representative species of the invention as compared to betamethasone 17-valerate. In this test, the drugs were administered intravenously to rats, while using a blank cotton pellet granuloma assay. Male Sprague-Dawley rats, each weighing about 185 grams (166-196 grams), were used. Two cotton pellets, each weighing 30 mg and containing no test compounds, were sterilized and implanted sub-cutaneously into the back of each test animal. This day was considered day 0 of implantation. Test compounds suspended in 0.8% polysorbate 80 were administered intravenously once daily for 3 consecutive days beginning with day 1. On day 5, the animals were sacrificed and the two pellets, with their respective granulomas, were removed, dried overnight in an oven at 50xc2x0 C. and weighed (dry granuloma weight). The thymi and final body weights were also recorded. The results are given in Table XI below.
In the foregoing tests, there was determined the deactivation of the representative species of the present soft steroids administered intravenously to rats. The ratio between the potencies of the test steroids and betamethasone 17-valerate against local anti-inflammation was 283:0.7 as seen from Table VI. This means that the test compounds exhibit a local anti-inflammatory activity which is approximately 400 times as high as the activity of the betamethasone 17-valerate. The test compounds were administered intravenously to rats to check the test compounds also for systemic anti-inflammatory activity as compared to betamethasone 17-valerate. The test compounds were found lower in the inhibition of granulation tissue formation and also in the thymus involution activity than betamethasone 17-valerate. From the results of the tests, it is presumed that the compounds which will not be readily subjected to metabolism (deactivation) have a systemic anti-inflammatory activity, as is the case with betamethasone 17-valerate.
The ED50 ""s calculated for the local cotton pellet granuloma assay (as shown, for example, in Table VI above) and the TED40""s calculated on the basis of thymus inhibition testing (as shown, for example, in Table X above) were used to arrive at relative potency and a therapeutic index for representative species of the invention as compared to prior art steroids. See Table XII below, which clearly shows the potent anti-inflammatory activity and minimal systemic toxicity of the compounds of the present invention.
The compounds of formula (I) can be combined with suitable non-toxic pharmaceutically acceptable carriers to provide pharmaceutical compositions for use in the treatment of topical or other localized inflammation. Obviously, in view of their lack of systemic activity, the compounds of the present invention are not intended for treatment of conditions where systemic adrenocortical therapy is indicated, e.g., adrenocortical insufficiency. As examples of inflammatory conditions which can be treated with pharmaceutical compositions containing at least one compound of the invention and one or more pharmaceutical carriers, the following can be mentioned: dermatological disorders such as atopic dermatitis, acne, psoriasis or contact dermatitis; allergic states such as bronchial asthma; ophthalmic and optic diseases involving acute and chronic allergic and inflammatory reactions; respiratory diseases; ulcerative colitis; and anorectal inflammation, pruritus and pain associated with hemorrhoids, proctitis, cryptitis, fissures, postoperative pain and pruritus ani. Such compositions may also be applied locally as a prophylactic measure against the inflammation and tissue rejection which arise in connection with transplants.
Obviously, the choice of carrier(s) and dosage forms will vary with the particular condition for which the composition is to be administered.
Examples of various types of preparations for topical/local administration include ointments, lotions, creams, powders, drops, (e.g. eye or ear drops), sprays, (e.g. for the nose or throat), suppositories, retention enemas, chewable or suckable tablets or pellets (e.g. for the treatment of aphthous ulcers) and aerosols. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents and/or glycols. Such base may thus, for example, include water and/or an oil such as liquid paraffin or a vegetable oil such as arachis oil or castor oil, or a glycolic solvent such as propylene glycol or 1,3-butanediol. Thickening agents which may be used according to the nature of the base include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycols, woolfat, hdyrogenated lanolin and beeswax and/or glyceryl monosterate and/or non-ionic emulsifying agents.
The solubility of the steroid in the ointment or cream may be enhanced by incorporation of an aromatic alcohol such as benzyl alcohol, phenylethyl alcohol or phenoxyethyl alcohol.
Lotions may be formulated with an aqueous or oily base and will in general also include one or more of the following, namely, emulsifying agents, dispersing agents, suspending agents, thickening agents, solvents, coloring agents and perfumes. Powders may be formed with the aid of any suitable powder base e.g. talc, lactose or starch. Drops may be formulated with an aqueous base also comprising one or more dispersing agents, suspending agents or solubilizing agents, etc. Spray compositions may, for example, be formulated as aerosols with the use of a suitable propellane, e.g., dichlorodifluoromethane or tricholorfluoromethane.
The proportion of active ingredient in the compositions according to the invention will vary with the precise compound used, the type of formulation prepared and the particular condition for which the composition is to be administered. The formulation will generally contain from about 0.0001 to about 5.0% by weight of the compound of formula (I). Topical preparations will generally contain 0.0001 to 2.5%, preferably 0.01 to 0.5%, and will be administered once daily, or as needed. Also, generally speaking, the compounds of the invention can be incorporated into topical and other local compositions formulated substantially as are such presently available types of compositions containing known glucocorticosteroids, at approximately the same (or in the case of the most potent compounds of the invention, at proportionately lower) dosage levels as compared to known highly active agents such as methyl prednisolone acetate and beclomethasone dipropionate or at considerably lower dosage levels as compared to less active known agents such as hydrocortisone.
Thus, for example, an inhalation formulation suitable for use in the treatment of asthma can be prepared as a metered-dose aerosol unit containing a representative species of the invention such as chloromethyl 17xcex1-ethoxycarbonyloxy-11xcex2-hydroxyandrost-4-en-3-one-17xcex2-carboxylate, according to procedures well-known to those skilled in the art of pharmaceutical formulations. Such an aerosol unit may contain a microcrystalline suspension of the aforementioned compound in suitable propellants (e.g., trichlorofluoromethane and dichlorodifluoromethane), with oleic acid or other suitable dispersing agent. Each unit typically contains 10 milligrams of the aforesaid active ingredient, approximately 50 micrograms of which are released at each actuation. When one of the more potent species of the invention, e.g. chloromethyl 17xcex1-ethoxycarbonyloxy-9xcex1-fluoro-11xcex2-hydroxy-16xcex1-methylandrosta-1,4-dien-3-one-17xcex2-carboxylate, is employed, each unit typically contains 1 milligram of the active ingredient and releases approximately 5 micrograms at each actuation.
Another example of a pharmaceutical composition according to the invention is a foam suitable for treatment of a wide variety of inflammatory anorectal disorders, to be applied anally or perianally, comprising 0.1% of a compound of formula (I) such as chloromethyl 17xcex1-ethoxycarbonyloxy-11xcex2-hydroxyandrost:-4-en-3-one-17xcex2-carboxylate, and 1% of a local anaesthetic such as pramoxine hydrochloride, in a mucoadhesive foam base of propylene glycol, ethoxylated stearyl alcohol, polyoxyethylene-10-stearyl ester, cetyl alcohol, methyl paraben, propyl paraben, triethanolamine, and water, with inert propellents. When a more potent compound of the invention is employed, less active ingredient generally is used, e.g. 0.05% of chloromethyl 9xcex1-fluoro-11xcex2-hydroxy-17xcex1-methoxycarbonyloxy-16xcex1-methylandrosta-1,4-dien-3-one-17xcex2-carboxylate.
Yet another pharmaceutical formulation according to the invention is a solution or suspension suitable for use as a retention enema, a single dose of which typically contains 40 milligrams of a compound of the invention such as chloromethyl 17-xcex1-ethoxycarbonyloxy-11xcex2-hydroxyandrost-4-en-3-one-17xcex2-carboxylate (or 20 milligrams of a more potent compound of the invention such as chloromethyl 9xcex1-fluoro-11xcex2-hydroxy-17xcex1-isopropoxycarbonyloxy-16xcex2- methylandrosta-1,4-dien-3-one-17xcex2-carboxylate or chloro-methyl 9xcex1-fluoro-11xcex2-hydroxy-16xcex1-methyl-17xcex1-propoxy-carbonyloxyandrosta-1,4-dien-3-one-17xcex2-carboxylate) together with sodium chloride, polysorbate 80 and from 1 to 6 ounces of water (the water being added shortly before use). The suspension can be administered as a retention enema or by continuous drip several times weekly in the treatment of ulcerative colitis.
Other pharmaceutical formulations according to the invention are illustrated in the examples which follow.